Parkinson?s disease (PD), known for over 2 centuries now, is the most common neurodegenerative movement disorder with no known cure as yet. PD is also the fastest growing neurological disorder globally in prevalence, disability and death and has devastating consequences to patients and families, in addition to the enormous economic burden. The well-described neuropathological hallmarks of PD are locomotion deficits, loss of dopaminergic neurons from substantia nigra and the formation of a-Synuclein (a-Syn) rich inclusions known as Lewy bodies. Interestingly apart from a-Syn, another highly conserved and very poorly understood family of human Tubulin-binding proteins, called the Tubulin Polymerization Promoting Proteins (TPPP) is implicated in PD and other synucleinopathies. Human TPPP is reported to have aggregation promoting properties and is a constituent in pathological protein deposits together with a-Syn in PD and related disorders such as Lewy body dementia and multiple systems atrophy. Importantly, there are no published knockout studies of any mammalian TPPP yet to better understand the genetics and neuropathology that might link TPPP aggregation and neurotoxicity to the pathogenesis of PD. Recently, we discovered the only Drosophila homolog of human TPPP named Ringmaker (Ringer) from a large-scale forward genetic screen. Our preliminary studies revealed that the adult TPPP/ringer mutants display reduced lifespan, severe locomotor disabilities, loss of dopaminergic neurons and deficits in mitochondrial structure and function. All of these phenotypes of ringer mutants resemble some of the salient features of human PD patients. The overall objective of this proposal is to develop a new model of PD utilizing Drosophila ringer mutants. Our central hypothesis is that Drosophila Ringer plays a key role in mitochondrial function and neurodegeneration. The hypothesis will be tested in two independent Specific Aims using genetic, cell biological, biochemical and behavioral experiments. In Aim 1, we will examine the progressive nature of the loss of DA neurons as well as other neuronal subtypes impacted in ringer mutant brain in addition to presence of any neuronal inclusions or aggregates. In Aim 2, we will explore the role of Ringer in mitochondrial structure and function and establish what role ringer might play with known PD-related a-Syn, pink1 and parkin genes. The proposal is highly innovative, feasible and timely, as it will utilize the only available in vivo Drosophila ringer mutant model to investigate its role in neurodegeneration and characterize the neuropathological phenotypes as well as explore its genetic and molecular underpinnings to provide insights into the role of human TPPP in PD and related neurodegenerative disorders. Importantly, this research will address a critical gap in our understanding of how this risk gene might contribute to exert toxicity in the brains of PD patients. Mechanistic insights gained from these studies, capitalizing on the strengths of Drosophila as a fast, relevant and inexpensive model system, might eventually shed light on potential therapeutic targets to either prevent or delay the progression of PD and related disorders.